Variant 4-143585942-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001168235.2(FREM3):c.6080G>A(p.Arg2027His) variant causes a missense change. The variant allele was found at a frequency of 0.0000683 in 1,537,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

FREM3
NM_001168235.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75

Variant links:

Genes affected

FREM3 (HGNC:25172): (FRAS1 related extracellular matrix 3) This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The protein belongs to the family of FRAS1/FREM extracellular matrix proteins and may play a role cell adhesion. [provided by RefSeq, Feb 2017]

FREM3 links:

GUSBP5 (HGNC:42319): (GUSB pseudogene 5)

GUSBP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08262846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM3	NM_001168235.2 linkuse as main transcript	c.6080G>A	p.Arg2027His	missense_variant	7/8	ENST00000329798.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FREM3	ENST00000329798.5 linkuse as main transcript	c.6080G>A	p.Arg2027His	missense_variant	7/8	5	NM_001168235.2	P1
GUSBP5	ENST00000641328.1 linkuse as main transcript	n.861+13361C>T		intron_variant, non_coding_transcript_variant
GUSBP5	ENST00000511042.5 linkuse as main transcript	n.191+13361C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000764

AC:

AN:

143930

Hom.:

AF XY:

0.0000913

AC XY:

AN XY:

76672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000473

Gnomad EAS exome

AF:

0.0000931

Gnomad SAS exome

AF:

0.0000880

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000690

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000693

AC:

AN:

1385290

Hom.:

Cov.:

AF XY:

0.0000644

AC XY:

AN XY:

683544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000357

Gnomad4 EAS exome

AF:

0.000560

Gnomad4 SAS exome

AF:

0.0000757

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000547

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.000155

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.6080G>A (p.R2027H) alteration is located in exon 7 (coding exon 7) of the FREM3 gene. This alteration results from a G to A substitution at nucleotide position 6080, causing the arginine (R) at amino acid position 2027 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.59

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.0063

Eigen

Benign

-0.012

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.013

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.57

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.080

REVEL

Benign

0.077

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Vest4

0.15

MVP

0.099

ClinPred

0.27

GERP RS

4.4

Varity_R

0.22

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over